A normal characteristic of hair growth in mammals, including humans, is that in most cases, the rate of hair growth and the length of its growth cycle are reduced with age. Those phenomena are common to all mammals with rare exceptions, and they must be differentiated from true male pattern alopecia, which is caused by target organ sensitivity to androgens.
Several factors may influence the rate of hair growth. These factors include race, sex, age, geography, season of the year, nutrition and hormones. See Myers, R. J. and Hamilton, J. B. "Regeneration and rate of growth of hairs in man" Ann. N.Y. Acad. Sci. 53:562-568 (1951); Hamilton, J. B. "Age, sex and genetic factors in the relation of hair growth in man: A comparison of Caucasian and Japanese populations" The Biology of Hair Growth (Ed. Montagna, W. and Ellis, R. A.), Academic Press Inc., New York, pp. 400-433 (1958); Yano, S. "Rate of hair growth" Hifu to Hinyo 4:546-552 (1936); Maeda, I. "Study on the cuticula of hair: (III) Relation between the cuticula and rate of the growth of human hair" Jyuzenkai-Zasski, 43:1298-1304 (1938); Trotter, M. "The resistance of hair to certain supposed growth stimulants" Arch. Dermatol. and Syphilol. 7:93-98 (1923); Pinkus, F. "Zur Kenntnis der Lebensdauer der menschlichen terminal haare" Z. Morphol. und Anthropol. 24:256-269 (1924); Ono, M. "Studies on the hair growth of beard and scalp hair (1st report) Influencing factor in the rhythms of hair growth" J. Physiol. Soc. Japan 25:254-261 (1963).
Various preparations have heretofore been proposed for the treatment of male pattern baldness. It is also a matter of common knowledge, however, that none of the so-called "hair growth formulae" have proven to be very efficacious.
In contrast to most epithelial structures, the hair follicle does not grow continuously throughout its life, but passes through a cycle called the pilar cycle. The pilar cycle comprises essentially three phases--namely, the anagen or growth phase during which hair is produced, normally lasting about three to seven years; the catagen phase when growth stops and the follicle atrophies, lasting about three to four weeks; and the telogen phase, which is a rest period for the follicle during which the hair progressively separates and finally falls out, and normally lasting about three to four months. Normally 80 to 95 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase. Whereas the telogen phase hair is uniform in diameter with a slightly bulbous, non-pigmented root, the anagen phase hair has a large colored bulb at its root.
Alopecia results when the pilar cycle is disturbed, resulting in excessive hair loss. The most frequent phenomenon is a shortening of the hair growth phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. This shortening of the growth or anagen phase of the pilar cycle may have different origins, among which are very diverse pathological origins such as febrile conditions, mental stresses, hormonal problems (such as androgenetic alopecia due to male hormones) and secondary effects of drugs. Alopecia may also be due to age and to a slowing down of mitotic activity. This dysfunction of the biological mechanism of hair growth leading to alopecia may be regarded as a disease. While there are other causes of alopecia such as greasy or oily scalp due to seborrhea and the dandruff accompanying it, the present invention is not directed to treating these extraneous causes of alopecia, but rather to treating the organic dysfunction of the hair follicle.
German Patent No. 2758484 discloses certain chemical preparations for treatment of scalp to prevent baldness. These preparations contain bile compounds as the active ingredients and also include pro Vitamin A or tretinoin. The active ingredient is a product obtained from gall or a derivative thereof such as chenodeoxycholic acid, urodoxy cholic acid and their salts or derivatives.
Another patent is Olsen U.S. Pat. No. 4,140,229 citing the use of Vitamin A-containing crystal clear, transparent, aqueous, sprayable emulsions for reducing itching and flaking of common dandruff and seborrhea. As stated in its abstract, in some instances, the use of such emulsions reduced excessive falling hair. It does not purport to stimulate hair growth. It simply teaches a method of conditioning hair and scalp to effect relief from dandruff symptoms. The only pertinent example in Olson is discussed under Case History No. 3 of Example IV wherein the "Spray-on-Brush-in-Solution" contained Vitamin A palmitate and seven other ingredients. All that is disclosed is that "the daily loss of head hair was reduced to approximately 10 to 20."
Knight British patent specification No. 1,466,062 discloses a cosmetic composition containing tocopherol and retinoic acid as a cosmetic preparation which can be used on the skin or as a hair cleaning or hair dressing agent. This multi-purpose cosmetic composition allegedly prevents age spots, and is claimed to be good for clearing the scalp of dandruff. It appears that, during clearing of the scalp of dandruff with this composition, the scalp can become healthier, hair loss is reduced, and hair growth can recommence. A specific treatment for androgenetic alopecia or male pattern alopecia is not suggested by this disclosure. The use of retinoids to alter the hair follicle growth rate or to prolong the anagen phase of the hair cycle is also not disclosed or discussed by Knight. Knight is claiming a cosmetic lotion for cleaning the scalp. Common dandruff and seborrhea or seborrheic dermatitis (seborrhea is the production of excess sebum and seborrheic dermatitis is an irritation of the scalp), as well as age spots, are the topic of this patent, and the composition used is a combination of two ingredients (Vitamin E and retinoic acid) in a cosmetic base.
There is a reference in the literature to the treatment of monilethrix using tretinoin (retinoic acid). Monilethrix is a vary rare genetic disease in which the hair shaft is defective and the hair is sparse and fragile. Topical application of retinoic acid improved the symptoms of this genetic defect. Hernandez-Perez, E. "Tretinoin therapy for monilethrix" Archives of Dermatology 109:575-576 (1974).
The use of retinoic acid in many disease conditions has been recently reviewed in the Journal of the American Academy of Dermatology by Haas and Arndt, "Selected therapeutic applications of topical tretinoin" 15:870-877 (1986). The review article in the May 1981 Journal of the American Academy of Dermatology, by Thomas, et al. also gives a list of the known uses of retinoic acid, but the treatment of alopecia or androgenetic alopecia is not listed.
There are no references of which I am aware for the use of retinoids in altering the rate of hair growth and treating alopecias, such as androgenetic alopecia. In fact, quite the opposite is the case, and the literature is full of references to hair loss caused by the toxic use of retinoids in high concentrations. References to hair loss caused by retinoids include W. Bollag and A. Matter, "From Vit A to Retinoids in Experimental and Clinical Oncology", p. 9-23, Modulation of Cellular Interactions by Vitamin A and Derivatives, (Retinoids) (Eds. Luigi M. DeLuca, Stanley S. Shapiro) Annals of New York Academy of Sciences, Vol. 359 (1981) and Retinoids: Advances in Basic Research and Therapy (Eds. C. E. Orfanos) Springer-Verlag (1981)--See articles "Aromatic Retinoids in Psoriasis", p. 165-173, S. Jablouska, et al.; and "Treatment of Severe Forms of Psoriasis and Retinoic Acid Derivatives", J. C. Gatti, et al., p. 185-191.
One compound, minoxidil, a potent anti-hypertensive compound, has been found to promote hair growth when applied topically to the scalp, as discussed in U.S. Pat. No. 4,139,619 and 4,596,812 to Chidsey et al. Minoxidil is recognized as being somewhat effective in producing new vellus hair growth and sparse terminal hair growth in a preselected group of subjects. However, its effect is far from satisfactory in most subjects.